bims-mecosi 2025-05-04 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–05–04
ten papers selected by
Verena Kohler, Umeå University

Artificial ER-Mitochondrion Tethering Restores Erg6 Localization and Lipid Droplet Formation in Hansenula polymorpha Δpex23 and Δpex29 Cells.
Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function.
Correlation of organelle interactions in the development of non-alcoholic fatty liver disease.
Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway.
Interaction vesicles as emerging mediators of host-pathogen molecular crosstalk and their implications for infection dynamics.
Mitochondrial Fusion Protein 2-Modified Bone Marrow Mesenchymal Stem Cells Improved Hyperglycemia-Induced Schwann Cell Injury via Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes.
The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria-ER membranes.
Inter-kingdom signaling by the Legionella autoinducer LAI-1 involves the antimicrobial guanylate binding protein GBP.
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.

Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251336908

Artificial ER-Mitochondrion Tethering Restores Erg6 Localization and Lipid Droplet Formation in Hansenula polymorpha Δpex23 and Δpex29 Cells.

Haiqiong Chen, Rinse de Boer, David C Lamb, Steven L Kelly, Ida J van der Klei.

  Pex23 proteins are a family of fungal endoplasmic reticulum proteins. Hansenula polymorpha contains four members, two of which, Pex24 and Pex32, function in endoplasmic reticulum-peroxisome membrane contact sites. In the absence of the other two members, Pex23 and Pex29, mitochondria are fragmented and lipid droplet numbers are reduced. We here show that in Δpex23 and Δpex29 cells an increased portion of the lipid droplet protein Erg6 (C24-methyltransferase), an enzyme involved in ergosterol biosynthesis, localizes to mitochondria. Erg6 relocalization and the reduction in lipid droplet numbers are suppressed by an artificial endoplasmic reticulum-mitochondrion tether protein. Sterol measurements showed that the presence of Erg6 at mitochondria did not cause major changes in the overall sterol composition. Our findings suggest that Pex23 and Pex29 play a role in endoplasmic reticulum-mitochondrion contact sites which prevent mitochondrial mislocalization of Erg6.

Keywords:  Erg6; Pex23; Pex29; lipid droplet; membrane contact sites; mitochondria

DOI:  https://doi.org/10.1177/25152564251336908
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141

Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.

Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.

  Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.

Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane

DOI:  https://doi.org/10.1177/25152564251332141
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251321770

Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function.

Emma J Fenech, Meital Kupervaser, Angela Boshnakovska, Shani Ravid, Inês Gomes Castro, Yeynit Asraf, Sylvie Callegari, Christof Lenz, Henning Urlaub, Peter Rehling, Maya Schuldiner.

  Membrane contact sites are molecular bridges between organelles that are sustained by tethering proteins and enable organelle communication. The endoplasmic reticulum (ER) membrane harbors many distinct families of tether proteins that enable the formation of contacts with all other organelles. One such example is the LAM (Lipid transfer protein Anchored at Membrane contact sites) family in yeast, which is composed of six members, each containing a putative lipid binding and transfer domain and an ER-embedded transmembrane segment. The family is divided into three homologous pairs each unique in their molecular architecture and localization to different ER subdomains. However, what determines the distinct localization of the different LAMs and which specific roles they carry out in each contact are still open questions. To address these, we utilized a labeling approach to profile the proximal protein landscape of the entire family. Focusing on unique, candidate interactors we could support that Lam5 resides at the ER-mitochondria contact site and demonstrate a role for it in sustaining mitochondrial activity. Capturing shared, putative interactors of multiple LAMs, we show how the Lam1/3 and Lam2/4 paralogous pairs could be associated specifically with the plasma membrane. Overall, our work provides new insights into the regulation and function of the LAM family members. More globally it demonstrates how proximity labeling can help identify the shared or unique functions of paralogous proteins.

Keywords:  ABOLISH; GRAMD/ASTER/STARD; LAM protein family; endoplasmic reticulum; membrane contact sites; proximity labeling

DOI:  https://doi.org/10.1177/25152564251321770
Front Immunol. 2025 ;16 1567743

Correlation of organelle interactions in the development of non-alcoholic fatty liver disease.

Jiabao Liao, Mengqiu Shao, Ze Zhou, Si Wang, You Lv, Yanming Lu, Fang Yao, Wenting Li, Ling Yang.

  Organelles, despite having distinct functions, interact with each other. Interactions between organelles typically occur at membrane contact sites (MCSs) to maintain cellular homeostasis, allowing the exchange of metabolites and other pieces of information required for normal cellular physiology. Imbalances in organelle interactions may lead to various pathological processes. Increasing evidence suggests that abnormalorganelle interactions contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the key role of organelle interactions in NAFLD has not been fully evaluated and researched. In this review, we summarize the role of organelle interactions in NAFLD and emphasize their correlation with cellular calcium homeostasis, lipid transport, and mitochondrial dynamics.

Keywords:  ER; MCSs; NAFLD; interactions; organelles

DOI:  https://doi.org/10.3389/fimmu.2025.1567743
Antioxidants (Basel). 2025 Apr 11. pii: 456. [Epub ahead of print]14(4):

Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway.

Wenwen Xing, Mengxuan Li, Binbin Wang, Lele Huo, Wanru Tian, Fangcai Ge, Manman Shen, Liumei Sun, Jiying Liu, Shali Yu.

  Oxidative stress (OS) is regarded as a major contributor to granulosa cellapoptosis in ovarian disease. 1-Deoxynojirimycin (1-DNJ), a naturally occurring plant alkaloid, exhibits antioxidant, anti-inflammatory, and metabolism-modulating properties. Mitochondria and endoplasmic reticulum (ER), crucial organelles regulating oxidative balance, interact through mitochondria-associated endoplasmic reticulum membranes (MAMs) for signaling and molecular exchange. However, it remains unclear whether 1-DNJ attenuates oxidative damage in ovarian granulosa cells (GCs) via MAMs-mediated ER-mitochondria crosstalk, which needs further exploration. This study aimed to investigate the mechanisms by which 1-DNJ affects oxidative damage and apoptosis induced by OS in porcine follicular GCs by regulating mitochondrial function, MAMs, and ER interactions. Here, we found that GCs suffered from OS, accompanied by the up-regulation of ROS and MDA, alongside reduced activity of antioxidant enzymes (CAT and T-SOD). Further studies revealed that the up-regulation of MAMs proteins (MFN2, MCU, and VDAC1) and pro-apoptosis proteins (BAX and Cleaved-capase3), along with increased mitochondrial ROS and Ca2+ levels, led to the down-regulation of MMP and ATP content. These, in turn, triggered mitochondrial dysfunction, and MAMs destabilization, and subsequent apoptosis. Additionally, the up-regulation of the protein levels of P-PERK/PERK, GRP78, ATF4, and CHOP protein expression activated the PERK-ATF4 signaling pathway, which triggered endoplasmic reticulum stress (ERS). Conversely, 1-DNJ alleviated H2O2-induced mitochondrial and MAMs dysfunction and ERS, which in turn attenuated apoptosis. Further, ATF4 knockdown inhibited MFN2 protein expression, which attenuated H2O2-induced MMP inhibition, Ca2+ overload, ROS production, and mitochondrial damage. In summary, 1-DNJ mitigated OS-induced mitochondrial dysfunction in GCs and regulated ER-mitochondrial communication through MAMs, reducing OS-induced apoptosis. The present study demonstrates that 1-DNJ protects ovarian GCs from OS-induced damage by modulating ER and mitochondrial homeostasis through MAMs, offering new perspectives and a theoretical basis for the treatment of ovarian diseases.

Keywords:  1-DNJ; endoplasmic reticulum stress; mitochondria-associated endoplasmic reticulum membrane; mitochondrial dysfunction; ovarian granulosa cells; oxidative stress

DOI:  https://doi.org/10.3390/antiox14040456
FEBS Lett. 2025 May 01.

Interaction vesicles as emerging mediators of host-pathogen molecular crosstalk and their implications for infection dynamics.

Bruna Sabatke, Izadora Volpato Rossi, Marcel I Ramirez.

  Extracellular vesicles (EVs) are critical in cell communication, transfer of biomolecules, and host-pathogen interaction. A newly identified subset, "interaction vesicles" (iEVs), forms through host-pathogen contact, merging membrane elements from both. These iEVs may arise through multiple mechanisms, including direct cell-cell contact, membrane contact sites, uptake and repackaging of foreign EVs, and post-release fusion of EVs. These hybrid vesicles enable pathogens to modify host environments, aiding immune evasion and infection persistence. However, iEVs may also act in favor of the host, contributing to pathogen recognition and elimination. Advanced techniques, including proteomics and high-resolution microscopy, are beginning to clarify their composition and fusion. Yet, isolating these hybrid EVs remains challenging. Overcoming these barriers could enhance understanding of infection mechanisms and support diagnostic and therapeutic innovation.

Keywords:  extracellular vesicles; host‐pathogen communication; immune evasion; infection persistence; interaction vesicles

DOI:  https://doi.org/10.1002/1873-3468.70055
Neurourol Urodyn. 2025 May 02.

Mitochondrial Fusion Protein 2-Modified Bone Marrow Mesenchymal Stem Cells Improved Hyperglycemia-Induced Schwann Cell Injury via Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes.

Housheng Fu, Zhewen Ou, Fei Wang, Weifu Wang, Zhongyao Wang.

   OBJECTIVE: High glucose damages rat Schwann cells (SCs), which is closely related to the dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAMs). Therefore, the present study aimed to investigate the protective effects and mechanisms of modified bone marrow mesenchymal stem cells (BMSCs) and mitochondrial fusion protein 2 (Mfn2) modified BMSCs against SCs injury.
METHODS: The Mfn2-modified BMSCs were constructed after culturing with neural-induced differentiation solution. MAP-2 (microtubule-associated protein-2, neuron marker) and GFAP (glial fibrillary acidic protein, astrocytes marker) immunofluorescence staining was used to observe changes in the differentiation potential of neural-like BMSCs. SCs (RSC96) cells cultured under high glucose conditions were cocultured with Mfn2-modified BMSCs. Changes in functional protein expression of MAMs were detected by Western Blot. Transmission electron microscopy (TEM) was used to observe the microscopic morphology of MAMs, mitochondria and endoplasmic reticulum.
RESULTS: The expression level of Mfn2 was significantly increased in BMSCs transfected with Mfn2. The fluorescence densities of MAP-2 and GFAP were significantly upregulated in Mfn2-BMSCs after induction by neural inducible differentiation solution. When RSC96 was incubated with high glucose and Mfn2-modified/non-modified BMSCs, the expression level of Mfn2 in RSC96 was significantly increased, while PERK, IP3R and Drp1 expressions were significantly reduced. And the Mfn2-modified BMSCs showed more significant effects comparing to Mfn2-non-modified BMSCs. The TEM showed the structural integrity of MAMs, clear structure of mitochondrial cristae and obvious and structurally intact extension of endoplasmic reticulum in Mfn2-BMSC group.
CONCLUSIONS: Mfn2 transfection promoted neural-like cell differentiation in BMSCs. Mfn2-modified BMSCs modulated the structural and functional homeostasis of MAMs by regulating the expression levels of MAMs functional proteins.

Keywords:  diabetic bladder dysfunction; mitochondrial fusion protein 2; mitochondria‐associated endoplasmic reticulum membranes

DOI:  https://doi.org/10.1002/nau.70067
NPJ Parkinsons Dis. 2025 Apr 30. 11(1): 103

The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria-ER membranes.

Peter A Barbuti, Cristina Guardia-Laguarta, Taekyung Yun, Zena K Chatila, Xena Flowers, Chantel Wong, Bruno F R Santos, Simone B Larsen, James S Lotti, Nobutaka Hattori, Elizabeth Bradshaw, Ulf Dettmer, Saranna Fanning, Vilas Menon, Hasini Reddy, Andrew F Teich, Rejko Krüger, Estela Area-Gomez, Serge Przedborski.

The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson's disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.

DOI: https://doi.org/10.1038/s41531-025-00960-x
PLoS Pathog. 2025 Apr;21(4): e1013026

Inter-kingdom signaling by the Legionella autoinducer LAI-1 involves the antimicrobial guanylate binding protein GBP.

Franziska Solger, Jonas Rauch, Simone Vormittag, Mingzhen Fan, Lyudmil Raykov, Paul Charki, Ana Katic, François Letourneur, Thierry Soldati, Jürgen Seibel, Hubert Hilbi.

The causative agent of Legionnaires' disease, Legionella pneumophila, is an amoebae-resistant environmental bacterium, which replicates intracellularly in a distinct compartment, the "Legionella-containing vacuole" (LCV). L. pneumophila employs the α-hydroxyketone compound LAI-1 (Legionella autoinducer-1) for intra-species and inter-kingdom signaling. LAI-1 promotes intracellular replication and inhibits the migration of mammalian cells and Dictyostelium discoideum. In this study, we revealed that LAI-1 and "clickable" azido-LAI-1 derivatives inhibit the migration of D. discoideum and localize to LCVs. Azido-LAI-1 colocalizes with the LCV markers calnexin, P4C, and AmtA, but not with mitochondrial or lipid droplet markers. Intriguingly, LAI-1-dependent inhibition of D. discoideum migration involves the single guanylate-binding protein (GBP), a member of the GBP family of large GTPases, which in metazoan organisms promote cell autonomous immunity. D. discoideum lacking GBP (Δgnbp) allows more efficient intracellular replication of L. pneumophila, without apparently compromising LCV formation or integrity, and GBP-GFP localizes to the ER at LCV-ER membrane contact sites (MCS). However, the peri-LCV localization of LAI-1 and GBP is not mutually dependent. Synthetic LAI-1 inhibits the expansion/remodeling of LCVs (but not vacuoles harboring avirulent L. pneumophila) in a GBP-dependent manner. Taken together, the work shows that LAI-1 localizes to LCVs, and LAI-1-dependent inter-kingdom signaling involves D. discoideum GBP, which localizes to LCV-ER MCS and acts as an antimicrobial factor by restricting the intracellular growth of L. pneumophila.

DOI: https://doi.org/10.1371/journal.ppat.1013026
Aging Cell. 2025 Apr 25. e70054

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.

Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.

  Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria

DOI:  https://doi.org/10.1111/acel.70054